SUMMARY We propose to develop a method to address the problem of the poor pharmacokinetics and resulting low efficacy of experimental therapies for acute kidney injury (AKI). AKI accounts for approximately 2% of hospital admissions in the United States and is associated with increased morbidity and mortality. The prevalence of AKI is up to 67% in patients admitted to intensive care, with 56% of those progressing to more advanced forms of the disease. Despite advances in the understanding of the epidemiology and pathogenesis of AKI, preventive measures remain inadequate and therapeutic approaches have largely proven futile. Multiple drug trials have been unsuccessful, mainly due to low drug specificity or poor pharmacokinetic profiles. Recently, we synthesized a novel nanoscale drug delivery platform that selectively targets the nephron (Williams, Nano Letters, 2015). We found that ?mesoscale? nanoparticles target the renal tubules and peritubular endothelium while bypassing other tissues in the body. The nanoparticles localize up to 25-fold more efficiently in the kidneys than in any other organ and release their drug cargo while exhibiting no toxic effects on the kidneys or other organs. This finding is unprecedented, and additional investigations are needed to assess its implications for the treatment of kidney diseases. We propose to investigate this technology to determine its route to the tubules, as well as its potential for treating AKI. In service of these these goals, we recently made two preliminary findings: We characterized in detail a route of entry for exogenous nanomaterials into the renal tubules and interstitium (Stamatiades, Cell, 2016) mediated by transport through the peritubular capillaries and monitored by resident macrophages. We hypothesize that our mesoscale nanoparticles internalize by this peritubular transport route. We propose to address this hypothesis herein. We successfully treated a murine model of AKI by targeting an ROS inhibitor specifically to the renal tubules. We administered mesoscale nanoparticles loaded with a radical scavenger, resulting in striking efficacy against a cisplatin-mediated model of AKI using a dose 154 times lower than that previously shown to treat AKI in a rodent model. We propose to investigate the mechanism of action of mesoscale nanoparticle-encapsulated ROS inhibitors and to assess their pharmacologic parameters and efficacy with respect to the inhibitors alone. In Aim 1 of the proposal, we will characterize the route of nanoparticle uptake in the renal interstitium and tubules. In Aim 2, we will assess the pharmacologic parameters of kidney-targeted ROS inhibitors. In Aim 3, we will assess the efficacy and therapeutic mechanism of tubule-specific ROS inhibitor therapy. Outcomes: These studies will address the unmet need for new methods to improve drug PK in the kidneys for the treatment of AKI by investigating mesoscale nanoparticle technology. We will determine the route of localization of this new drug delivery vehicle to the kidneys, its ability to modulate drug PK, and its potential to improve therapeutic index of drugs for the treatment of AKI in patients.